MAFA and T3 Drive Maturation of Both Fetal Human Islets and Insulin-Producing Cells Differentiated From hESC
MAFA and T3 Drive Maturation of Both Fetal Human Islets and Insulin-Producing Cells Differentiated From hESC
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DOI：
10.1210/jc.2015-2632
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发表时间：
2015-10-01
影响因子：
5.8
通讯作者：
Bonner-Weir, Susan
中科院分区：
文献类型：
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作者：
Aguayo-Mazzucato, Cristina;Dilenno, Amanda;Bonner-Weir, Susan
背景：人胚胎干细胞(HESCs)分化为β细胞和胚胎人胰岛细胞在转录水平上相似，其特点是不成熟，缺乏葡萄糖反应，胰岛素含量低，胰岛素原-胰岛素加工障碍。然而，它们对促进功能的刺激的反应还没有被比较。目的：本研究的目的是评估我们以前开发的啮齿动物功能成熟策略在这两种人类β细胞不成熟模型中的效果，并比较它们的反应。设计、设置、参与者和干预：在验证性实验中，使用腺病毒介导的V-Maf过表达禽肌腱膜纤维肉瘤癌基因同源A(MAFA)或通过甲状腺激素(T-3)和人胎儿胰岛样簇(ICC)的生理驱动途径(T-3)进行功能成熟评估。主要观察指标：葡萄糖反应性、胰岛素含量、成熟β细胞转录因子MAFA的表达和胰岛素原处理情况。结果：ICCS对MAFA过度表达和T-3处理的反应均为阳性，通过两个不同的成熟参数评价：16.8 mM葡萄糖时胰岛素分泌增加和胰岛素原处理增加。在分化为β细胞的hESCs中，T-3促进MAFA的表达，增加胰岛素含量(可能由MAFA增加所介导)，并增加16.8 mM葡萄糖的胰岛素分泌。结论：T-3是一种有用的刺激因素，可促进人胚胎ICCs和分化的hESCs的β细胞成熟。两种模型所诱导的成熟程度不同，可能是由于研究开始时发育状况不同所致。
Context: Human embryonic stem cells (hESCs) differentiated toward beta-cells and fetal human pancreatic islet cells resemble each other transcriptionally and are characterized by immaturity with a lack of glucose responsiveness, low levels of insulin content, and impaired proinsulin-to-insulin processing. However, their response to stimuli that promote functionality have not been compared.Objective: The objective of the study was to evaluate the effects of our previous strategies for functional maturation developed in rodents in these two human models of beta-cell immaturity and compare their responses.Design, Settings, Participants, and Interventions: In proof-of-principle experiments using either adenoviral-mediated overexpression of V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) or the physiologically driven path via thyroid hormone (T-3) and human fetal islet-like cluster (ICC) functional maturity was evaluated. Then the effects of T-3 were evaluated upon the functional maturation of hESCs differentiated toward beta-cells.Main Outcome Measures: Functional maturation was evaluated by the following parameters: glucose responsiveness, insulin content, expression of the mature beta-cell transcription factor MAFA, and proinsulin-to-insulin processing.Results: ICCs responded positively to MAFA overexpression and T-3 treatment as assessed by two different maturation parameters: increased insulin secretion at 16.8 mM glucose and increased proinsulin-to-insulin processing. In hESCs differentiated toward beta-cells, T-3 enhanced MAFA expression, increased insulin content (probably mediated by the increased MAFA), and increased insulin secretion at 16.8 mM glucose.Conclusion: T-3 is a useful in vitro stimulus to promote human beta-cell maturation as shown in both human fetal ICCs and differentiated hESCs. The degree of maturation induced varied in the two models, possibly due to the different developmental status at the beginning of the study.